In a landmark development poised to reshape the landscape of hepatocellular carcinoma (HCC) treatment, researchers have unveiled compelling data from the ReUNION-1 phase 2 trial, exploring the synergistic potential of stereotactic body radiotherapy (SBRT) combined with the immunotherapeutic agent sintilimab and a bevacizumab biosimilar in patients resistant to anti-PD-1 therapies. As HCC remains one of the most lethal malignancies worldwide with limited effective salvage options following immune checkpoint inhibitor failure, this multi-modal approach signals a breakthrough that could redefine therapeutic strategies for this aggressive cancer variant.
Hepatocellular carcinoma, the predominant form of liver cancer, is notorious for its poor prognosis and frequent resistance to conventional treatments. Immunotherapy, particularly agents targeting the PD-1/PD-L1 axis, has revolutionized oncological care in recent years, granting relief and remissions previously unseen in systemic management. However, a substantial subset of patients develops resistance or exhibits primary refractoriness to PD-1 inhibitors, underscoring an urgent need for new interventions that circumvent or overcome this immunoresistance.
The ReUNION-1 trial uniquely integrates stereotactic body radiotherapy, an advanced form of radiation delivering precise, high doses to tumor tissues while sparing surrounding normal structures, with an immunomodulatory duo: sintilimab — a PD-1 blocking antibody — and a bevacizumab biosimilar, an anti-VEGF agent that inhibits tumor angiogenesis. This combinatorial regimen aims to harness radiotherapy-induced immunogenic cell death and normalize the tumor microenvironment’s vasculature, potentially enhancing immune cell infiltration and reinvigorating exhausted T-cell responses in a subset of patients who had previously failed anti-PD-1 monotherapy.
Technically, SBRT capitalizes on image-guided radiation techniques, allowing for delivery of ablative doses ranging typically between 30 to 50 Gy in a few fractions. This concentrated energy disrupts tumor DNA and triggers release of tumor-associated antigens, promoting the recruitment and activation of dendritic cells. When combined with checkpoint inhibitors such as sintilimab, this mechanism can potentiate systemic antitumor immunity, a principle often referred to as the abscopal effect. The addition of bevacizumab biosimilar compounds this effect by targeting VEGF-mediated pathways that foster immunosuppression via aberrant angiogenesis and stromal remodeling, thereby reversing immune exclusion phenomena.
The ReUNION-1 trial enrolled a cohort of patients with advanced or metastatic HCC who exhibited clear progression after anti-PD-1 therapies. Over the course of the study, participants underwent SBRT targeting primary tumors or metastatic sites, followed by systemic administration of sintilimab and the bevacizumab biosimilar. Efficacy metrics, including objective response rates, progression-free survival, and overall survival, were meticulously evaluated alongside biomarkers of immune activation and angiogenesis.
Remarkably, the trial reported encouraging objective response rates, with a significant proportion of patients achieving partial or complete tumor regression despite prior resistance to PD-1 inhibition. Imaging analyses revealed not only local tumor control but also evidence of systemic disease stabilization, a hallmark of effective immuno-radiotherapeutic synergy. These results underscore the potential of combining physical tumor debulking and immunomodulatory therapies to reset the tumor-immune equilibrium even in therapy-refractory contexts.
Safety profiles were carefully monitored, revealing tolerability consistent with previous experiences of both SBRT and immune checkpoint inhibition. Adverse events predominantly included manageable immune-related toxicities and transient radiation-induced inflammation without unexpected severe complications. This favorable safety spectrum enhances the clinical feasibility of this regimen, particularly in patients with compromised hepatic function and limited treatment reserve.
From a mechanistic standpoint, translational studies accompanying the clinical trial offer intriguing insights into tumor microenvironment remodeling. Post-treatment biopsies demonstrated increased infiltration of CD8+ cytotoxic T lymphocytes and decreased markers of hypoxia and angiogenic signaling. These molecular signatures suggest that the combined modality therapy not only eradicates tumor cells but remodels the immunosuppressive niche that otherwise shields HCC from immune attack.
Furthermore, exploratory analyses hinted at potential predictive biomarkers for response, including baseline VEGF levels and specific immune-related gene expression profiles. Such findings could pave the way toward personalized treatment algorithms, helping stratify patients who are most likely to benefit from this innovative combinational strategy.
The implications of the ReUNION-1 trial extend beyond hepatocellular carcinoma alone. The paradigm of leveraging multi-modal immuno-radiotherapy could be applicable to various solid tumors where immune checkpoint blockade faces limitations. By integrating targeted radiation with dual immune and anti-angiogenic modulation, this approach harnesses complementary mechanisms to overcome tumor heterogeneity and adaptive resistance, shifting the therapeutic horizon.
Ongoing follow-up and larger randomized studies are warranted to validate these findings, refine dosing schedules, and optimize patient selection criteria. Nonetheless, the current data marks a critical step forward in the quest to improve outcomes for patients with refractory HCC, a group traditionally confronted with dismal survival prospects.
In sum, the ReUNION-1 phase 2 trial delineates a potent new frontier in cancer therapy at the intersection of precision radiotherapy and cutting-edge immunotherapy. By transforming a once-dismal treatment landscape into one of dynamic immunologic engagement and tumor control, it offers renewed hope for patients and clinicians battling hepatocellular carcinoma resistant to established immune checkpoint blockade.
As cancer research continues to evolve rapidly, the integration of advanced radiation techniques with novel biologic agents exemplifies the innovative spirit driving the field. Trials like ReUNION-1 highlight the promise of combinational regimens tailored to overcome resistance mechanisms, potentially setting a new standard of care for notoriously intractable malignancies.
With further scientific refinement and clinical validation, such combinatory strategies could transcend current therapeutic limitations, heralding an era where durable tumor control and prolonged survival become achievable realities for patients historically defined by poor prognosis. The ongoing venture into synergistic immuno-radiotherapy thus stands as a beacon of progressive cancer care innovation, meriting close attention from the oncology community worldwide.
Subject of Research: Hepatocellular carcinoma treatment using stereotactic body radiotherapy in combination with sintilimab and a bevacizumab biosimilar in patients refractory to anti-PD-1 therapy
Article Title: Stereotactic body radiotherapy with sintilimab and bevacizumab biosimilar in anti-PD-1 refractory hepatocellular carcinoma: the ReUNION-1 phase 2 trial.
Article References:
Tang, J., Yang, Y., Liu, D. et al. Stereotactic body radiotherapy with sintilimab and bevacizumab biosimilar in anti-PD-1 refractory hepatocellular carcinoma: the ReUNION-1 phase 2 trial. Nat Commun (2025). https://doi.org/10.1038/s41467-025-67528-4
Image Credits: AI Generated
